tbuckley/cabot-search huggingface dataset:
Association between social determinants of health and outcomes among young patients with prostate cancer.
Authors: Oluwasegun Akinyemi, Terhas Weldeslase, Faith Abodunrin, Oluwatayo Adeoye, Peter T. Silberstein, Adam Metwalli
Journal: Journal of Clinical Oncology (2023)

e18500 Background: Influence of Social Determinants of Health (SDHs) on Outcomes among Young Patients with Prostate Cancer. SDHs significantly influence prostate cancer patients' incidence, presentation, and outcomes. However, how these factors affect outcomes in younger patients with prostate cancer has been understudied in the literature. Prostate cancer is the commonest cancer among men in the US, and studying these factors will further enhance efforts to develop appropriate public health strategies to combat the disease. Aim: To determine the influence of patients' race and SDHs on outcomes among young patients with prostate cancer. Methods: Utilizing data from the National Cancer Database (NCDB), we conducted a retrospective analysis of all patients with a primary diagnosis of prostate cancer from January 2004 to December 2018. The outcome measures were diagnosis to definitive treatment time (days), length of hospitalization (days), and overall survival. We determined the influence of patients’ race/ethnicity, insurance type, residence annual median income (median household income for each patient's area of residence), and residence education level (defined as the proportion of adults ≥25 years who did not complete high school in the patients' zip code) on the overall survival among young patients with prostate cancer. Results: There were 843,511 cases of prostate malignancy reported in the National Cancer Database between 2004 and 2018. About 6.3% of these patients were younger than 50 years (N=52,890). Among the younger patients, 74.0% were whites, and 21.3% were Blacks. These compare to the control of adults older than 50 years, with 84.3% whites and only 11.3% Blacks. On multivariate analysis, Black patients have a longer diagnosis to definitive treatment time and overall longer hospital stay but no racial disparity in overall survival. Significant predictors of overall survival among the young prostate cancer survivors were patients with private insurance and higher income quintiles (see table). Conclusions: Insurance and income rather than race/ethnicity or education level appear to constitute a significant predictor of survival among young prostate cancer patients in the United States.[Table: see text]
A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.
Authors: Sarmad Sadeghi, Melissa Plets, Primo N Lara, Catherine Tangen, Rick Bangs, Seth P. Lerner, Thomas W. Flaig, Daniel P. Petrylak, Ian M Thompson
Journal: Journal of Clinical Oncology (2023)

TPS4608 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Clinical trial information: NCT04579224 .
First-in-human clinical trial design of a first-in-class theranostic approach with a peptide-based radioligand targeting CA IX-expressing tumors.
Authors: Darren R. Feldman, Ben Tran, Louise Emmett, Michael S Hofman, Pierre Olivier, Hakim Mahammedi, Ivana Galetic, Anna Pokorska-Bocci, Florilene Bouisset, Kathrin Gollmer, Mariya Pavlyuk, Libuse Tauchmanova, Ken Herrmann
Journal: Journal of Clinical Oncology (2023)

TPS3160 Background: Expression of carbonic anhydrase IX (CA IX), a cell surface glycoprotein, can be induced by a state of hypoxia or by mutation of the Von Hippel-Lindau tumor suppressor gene. CAIX expression in tumors is often associated with progressive disease and overall poor outcomes in various solid cancers. Notably, high CA IX expression has been observed in 83%, 40%, and 29% of clear cell renal cell carcinoma (ccRCC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) specimens, respectively 1 . CA IX may therefore represent a valuable therapeutic target. DPI-4452 is a first-in-class cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([ 68 Ga]Ga-DPI-4452) or lutetium-177 ([ 177 Lu]Lu-DPI-4452) is an innovative theranostic approach for identifying and treating patients (pts) with CA IX-expressing tumors. Pre-clinical data has shown that [ 177 Lu]Lu-DPI-4452 is taken up by tumors and induces dose-dependent growth inhibition in ccRCC and CRC xenograft mouse models 1,2 . Methods: We present the design of a Phase I/II study (NCT05706129) of [ 68 Ga]Ga-DPI-4452 and [ 177 Lu]Lu-DPI-4452 in pts with unresectable locally advanced or metastatic ccRCC, CRC or PDAC. The study is comprised of three phases: imaging (Part A), dose-escalation (Part B), and expansion (Part C). In Part A, pts will receive a single intravenous (IV) 185 MBq dose of [ 68 Ga]Ga-DPI-4452. Safety, tolerability, pharmacokinetics (PK), dosimetry and imaging characteristics of [ 68 Ga]Ga-DPI-4452 will be evaluated using positron emission tomography/computed tomography (CT) at four timepoints on Day 1. All pts will be followed for seven days post-injection for safety observations. In Part B, based on [ 68 Ga]Ga-DPI-4452 uptake, pts will receive sequential, escalating doses of IV [ 177 Lu]Lu-DPI-4452 on Day 1 of each 28-day cycle for up to eight cycles. During Cycle 1, each pt will undergo up to four whole-body planar imaging and single photon emission CT/CT analyses for dosimetry over seven days. In Part B, the recommended Phase 2 dose of [ 177 Lu]Lu-DPI-4452 will be determined, guided by a Bayesian Logistic Regression model. Safety, PK, and dosimetry will be assessed to minimize any radiation-induced toxicity and to optimize absorbed radiation dose in the tumor. Upon completion of Part B, Part C will enroll up to three cohorts of pts with CA IX-positive ccRCC, CRC or PDAC to assess preliminary efficacy of [ 177 Lu]Lu-DPI-4452, with a primary endpoint of objective response rate, as measured by RECIST v1.1. References Wiedemann N et al. J Nucl Med 2022;63(Suppl 2):4048. Attinger A et al. Eur J Nucl Med Mol Imaging 2022;49(Suppl 1):S1–S751. Clinical trial information: NCT05706129 .
Comparison of multi-omics biomarkers via liquid biopsy in early detection of gastric cancer.
Authors: Xuefei Wang, Zhaoqing Tang, Yanan Wang, Jinyu Yang, Zhongyi Shi, Dan Liu, Qiaoxia Zhou, Yu Xu, Fujun Qiu, Yuan Gu, Lingqiang Min, Chen Ding, Peng Zhou, Yihong Sun
Journal: Journal of Clinical Oncology (2023)

e16066 Background: Effective and convenient early detection methods are still lack for gastric cancer. Liquid biopsy, by detecting cell-free DNA (cfDNA) methylation, circulating tumor DNA (ctDNA) mutation, and serum protein markers etc., may provide a non-invasive method to early detect cancer. However, head-to-head comparison of these biomarkers have not been studied. Here, we report the results of the Assessment of Early-Detection Based on Liquid Biopsy in Gastric Cancer (ASCEND-GASTRIC, NCT05224596), a case-control study to early detect gastric cancer via cfDNA methylation, ctDNA mutation, and pre-specified serum protein markers. Methods: Blood samples from gastric cancer patients were prospectively collected from the Department of General Surgery of Zhongshan Hospital, Fudan University. Blood samples from age-matched healthy controls were also prospectively collected. Blood samples were subjected to a methylation panel of ~490,000 CpG sites sequenced by the ELSA-seq, a mutation panel of ultra-deep sequenced 168 genes, and tumor protein assays. All blood samples (cancer, n=134; healthy control, n=330) were randomly assigned into the training and the test sets. Results: In the training set, cfDNA methylation and ctDNA mutation efficiently discerned cancer patients from healthy controls, while the commonly used protein markers of gastric cancer were not significantly higher in the cancer patients than in the healthy controls. In the test set, cfDNA methylation achieved 65.6% sensitivity (95% confidence interval [CI], 52.5%‒77.1%) at 96.8% specificity (95% CI, 89.9%‒100%), while ctDNA mutation exhibited lower sensitivity of 16.5% (95% CI, 9.1%‒26.5%) at 95.9% specificity (95% CI, 86.0%–99.5%). On top of the methylation-based model, the mutation-based model slightly increased sensitivity (70.7%; 95% CI, 57.3%‒81.9%) at the cost of reduced specificity (91.8%; 95% CI, 80.4%‒97.7%). Conclusions: In this study, cfDNA methylation exhibited better effectiveness than ctDNA mutation and serum protein markers in the early detection of gastric cancer. Based on cfDNA methylation, ctDNA mutation might not further provide value for the detection of gastric cancer. Our study highlights the potential clinical utility of the methylation-based early detection model for gastric cancer. A further expanded validation study is ongoing. Clinical trial information: NCT05224596 . [Table: see text]
Immune checkpoint inhibitors (ICIs) with or without anti-angiogenic agents (AAAs) and cardiovascular toxicity: A meta-analysis.
Authors: Giorgio Madonia, Antonello Veccia, Alvise Berti, Orazio Caffo, Antonio Russo, Stefania Gori, Alessandro Inno
Journal: Journal of Clinical Oncology (2023)

e24084 Background: ICIs have extended survival across many tumor types at the cost of immune-related adverse events (irAEs) that can involve any organ or system, including cardiovascular system. Emerging evidence suggest that ICIs may have a role in promoting the atherosclerotic plaque progression, thus leading to acute vascular events (AVEs) This may represent a concern when combining ICIs with other anti-cancer agents burdened by cardiovascular toxicity, such as anti-angiogenic agents (AAAs), that are associated with increased risk of hypertension (HTN) and AVEs. In the present meta-analysis, we aimed to evaluate the odds of adverse events (AEs), irAEs, HTN and AVEs with ICI+AAAs, as compared with AAAs alone. Methods: Phase III randomized controlled trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception until June 2022. Systematic review and metanalysis were conducted according to PRISMA guidelines. AEs, irAEs, HTN and AVEs were collected (main outcomes of this metanalysis), objective response rate (ORR) and progression free survival (PFS) were also collected (secondary outcomes). AVEs were defined as stroke, myocardial infarction, thrombotic events, pulmonary embolism. Severe AEs, irAE, HTNs and AVEs were defined as grade ≥3 according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE) version 4.0 or 4.03, as reported in each trial. Results: Twelve trials with a total of 8124 patients (4159 in the experimental arms and 3965 in the control arms) were included in the meta-analysis. The addition of ICIs to AAAs did not increase the rate of AEs (any grade, OR 1.15, 95%CI 0.71-1.85; severe, OR 1.18, 95% CI 0.96-1.44). In contrast, the incidence of irAE was significantly higher in the ICIs+AAA- group versus AAAs (any grade: OR 1.97, 95%CI 1.21-3.21, p = 0.007; severe: OR 3.20, 95%CI1.41-7.29, p = 0.006), as expected. There was no difference in terms of any grade HTN between the 2 groups (OR 1.17, 95%CI 0.91-1.50, p &gt; 0.05), but severe HTN was higher among patients treated with ICIs+AAAs as compared with those receiving AAAs alone (OR 1.24, 95%CI 1.01-1.53, p = 0.04). AVEs rates were low in both groups (2.2% and 1.9% for ICI+AAA and AAA alone, respectively). A subset analysis of trials specifically reporting AVEs did not show any increase in ICIs+AAAs versus AAAs alone (any grade: OR 1.21, 95%CI 0.68-2.16, p &gt; 0.05; severe: OR 1.14, 95%CI 0.61-2.15, p &gt; 0.05). Overall, the ORR and PFS were higher in the ICIs+AAAs group as compared to AAAs alone (OR 2.25, 95%CI 1.70-2.97, p &lt; 0.001; OR 4.37, 95%CI 2.91-5.83, p &lt; 0.001, respectively). Conclusions: The addition of ICIs to AAAs significantly increased the risk for irAEs and severe HTN, but not the risk for AVEs.
The impact of cancer prehabilitation on psychological outcomes and quality of life in patients with gastro-oesophageal cancer.
Authors: Laura Halliday, Krishna Moorthy, Alex King, Venetia Wynter-Blyth, Bernarda Zamora Zamora Talaya
Journal: Journal of Clinical Oncology (2023)

e16096 Background: The impact of cancer on psychological health and health related quality of life (HRQoL) is complex and involves an interaction between pre-existing and cancer related psychological morbidity and symptoms. Factors such as self-efficacy are known predictors of recovery and HRQoL. The aim of this study is to assess the impact of multi-modal personalised prehabilitation on psychological outcomes and HRQoL in patients with curable oesophageal and gastric (OG) cancer. Methods: Data was collected for to all patients treated at a specialist centre between Jan 2016 and June 2018. Patients received multi-modal (physical, nutrition and psychological) prehabilitation from diagnosis into the post-operative period. Data on self-efficacy (SE), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and HRQoL (European Organization for Research and treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)) were collected at diagnosis (T1), completion of neo-adjuvant chemotherapy (T2) and 3 months after surgery (T3). A previously validated mapping function was used for predicting Euro QoL 5D-3L (EQ-5D-3L) from scale scores of the EORTC QLQ-C30 instrument to derive a EQ health utility (EQ-HU). Results: 137 patients underwent surgery. 86 patients underwent a thoracotomy in addition to a laparotomy. 107 patients received neo-adjuvant treatment. There was a significant improvement in SE [8.2 (6.2-9) to 8.8 (7.8-9.7); p = 0.002] and anxiety [5 (3-8) to 4 (2,7); p = 0.04] but not depression [2 (1-5) to 3 (1-5); p = 0.26] between T1 and T2. There were no differences between T2 and T3. There were no differences in global HRQoL and the individual scales of the EORTC QLQ-C30 between T1 and T2. However, between T2 and T3, there were significant reductions in global HRQoL [69.6 (18.2) to 64.7 (20.9); p = 0.04], physical [83.2 (18.2) to 70.9 (20.5); p = 0.001], role [79 (28.6) to 70.9 (28.3; p = 0.02], cognitive [84.2 (22.3) to 76 (23.3); p = 0.004] and social [79 (24.2) to 65.5 (26.1); p = 0.001] but not emotional functions [80.1 (21.4) to 79.5 (23.3); p = 0.67]. Mapping revealed that there was a significant improvement in EQ-HU from T1 to T2 [0.54 (0.52) to 0.79 (0.34); p = 0.001] and a significant fall from T2 to T3 [ 0.79 (0.34) to 0.58 (0.44); p = 0.001]. The minimum and maximum predicted values matched those of the validated mapping function used. Conclusions: This study shows that prehabilitation can have a significant impact on HU in patients on chemotherapy. Despite the well-recognised limitations of mapping, HU at baseline was comparable to that shown in previous research in OG cancer patients. Reduction in HRQoL seen after surgery was much less than previously published research, suggesting the protective effect of prehabilitation. Physical function deterioration, in particular was much less than anticipated.
Induction chemotherapy plus definitive chemoradiotherapy versus chemoradiotherapy alone in esophageal squamous cell carcinoma: Long-term results and exploratory analyses of a randomized controlled trial.
Authors: Mian Xi, BaoQing Chen, Shi-Liang Liu, Yujia Zhu, Lei Zhao, Mengzhong Liu
Journal: Journal of Clinical Oncology (2023)

4061 Background: The previous results of our trial demonstrated that the addition of induction chemotherapy (IC) prior to definitive chemoradiotherapy (CRT) failed to significantly improve response rate or 3-year survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Here, we report the long-term results and exploratory analyses to further evaluate the therapeutic value of IC in ESCC. Methods: This was a single-institution, open-label, randomized, phase II trial. Patients with previously untreated, unresectable, stage II–IVA ESCC were randomly assigned in a 1:1 ratio to receive induction docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1) every 3 weeks for two cycles, followed by concurrent CRT, or CRT alone. The primary endpoint was overall response rate at 3 months after CRT. Second endpoints were overall survival (OS) and progression-free survival (PFS). The relationship between tumor response to IC and long-term survival was analyzed as an exploratory, post-hoc analysis. Moreover, baseline tumor biopsies were evaluated by RNA-seq to identify patients who are more likely to benefit from IC. Results: Between May 2015 and September 2017, 110 eligible patients were randomly assigned to the IC+CRT group (n=55) or the CRT group (n=55). The overall response rate was 74.5% in the IC+CRT group versus 61.8% in the CRT group (P=0.15). At a median follow-up of 74.9 months, the 5-year OS rate was 31.8% in the IC+CRT group and 29.1% in the CRT group (P=0.68; HR, 0.91; 95% CI, 0.58–1.43). Similarly, no significant differences were identified in 5-year PFS between groups (30.5% vs. 25.5%, P=0.51; HR, 0.86; 95% CI, 0.56 to 1.34). Patients who responded to IC had significantly better survival than nonresponders. Six key genes were identified based on RNA-seq and gene expression comparison between responders and nonresponders after IC. Risk-score model was constructed by these key genes and then validated. Conclusions: Addition of induction docetaxel plus cisplatin before definitive CRT still failed to provide an obvious survival benefit in ESCC based on long-term follow-up. However, this strategy did result in a significantly improved survival in IC responders. Our results also revealed potential molecular biomarkers to predict who may benefit from IC. Clinical trial information: NCT02403531.
Continuous dosing of AUM001 with cyclical gemcitabine/nab-paclitaxel to maintain the tumor growth kinetics in KPC xenograft model.
Authors: Balram Chowbay, Wai Fook Leong, Sze Sing Lee, Jyue Yuan Lim, Romana Vidergar, Wai Meng David Tai, Subhra Kumar Biswas
Journal: Journal of Clinical Oncology (2023)

e15112 Background: PDAC is a highly desmoplastic and aggressive disease with limited therapeutic options and poor 5-year survival outcome. Gemcitabine (GEM) plus nab-paclitaxel (nPTX) is widely used as a first line treatment for PDAC but advancement for greater improvement on efficacy is still warranted. Dysregulated mRNA translation of pro-tumorigenic genes has contributed to the proliferative and metastatic nature of PDAC. Targeting oncogenic mRNA translation via MNK-coupled phosphorylation of eIF4E could serve as a target for inhibition to synergize chemotherapy. AUM001 is a novel MNK1/MNK2 inhibitor undergoing clinical trials in various solid tumors. We hypothesize that combination of AUM001 with GEM-nPTX would have synergistic effect in modulating the tumor growth kinetics and maintaining the tumor in a stable state. Methods: PDAC KPC cells were subcutaneously implanted into BL6 mice and randomized into five treatment groups once tumor volumes of 60-80mm 3 were reached. Saline (control), GEM-nPTX were administered intraperitoneally on days 1, 4 and 8 while AUM001 was given orally on a daily basis for 8 days. The combination of GEM-nPTX and AUM001 were administered at similar doses and frequency. AUM001 was given for another 3 weeks in the continuous dosing group. Body weight and tumor volume were measured thrice weekly. Immunohistochemistry staining was performed on FFPE sections for Ki67, angiogenesis and stromal markers. Apoptosis was analyzed by Annexin V-propidium iodide flow cytometric assay. P &lt; 0.05 was considered as statistically significant. Results: GEM-nPTX and AUM001 (GPA) or GEM-nPTX (GP) alone resulted in approximately 30% reduction in relative tumor volume. The continuous dosing of AUM001 (GPAc) after the cessation of chemotherapy showed a marked 55% decline in relative tumor volume ( P= 0.0079) compared to GPA. The phosphorylation of EIF4E (target of MNK1/2) and Myc expression were significantly inhibited in GPAc vs GPA groups at end of observation (EOO) (P &lt; 0.05). VEGFA expression at EOO was found to be suppressed in GPAc compared to GPA group ( P= 0.0159) with no difference in MVD ( P&gt; 0.05). Greater fraction of apoptotic cells was detected in GPAc at EOO ( P= 0.055) than GPA ( P&gt; 0.999) when referenced to GP group. Conclusions: This study demonstrated that continuous dosing of AUM001 with cyclical GEM-nPTX is well-tolerated and confers good anti-tumor effect. Pharmacodynamic analysis also suggests that AUM001 may potentiate the reduction in pro-tumorigenic protein expression. This is the first study depicting the continuous dosing of AUM001 after cessation of chemotherapy could help to maintain the tumor state, facilitating its possible use in clinics as maintenance therapy in PDAC.